This invention relates to the use of a therapeutic combination of nociceptive compounds to treat pain. The method of pain treatment comprises concurrent administration of a hydroxyazapirone selected from 6-hydroxybuspirone or 3-hydroxygepirone with acetaminophen (paracetamol). This combination of agents produces a more robust analgesic response with rapid onset.
Acetaminophen is an established analgesic agent having only weak anti-inflammatory activity and can be classified as a non-NSAID analgesic. Ibuprofen is an example of a non-steroidal analgesic having significant anti-inflammatory properties and is classified as a non-steroidal anti-inflammatory drug (NSAID). Acetaminophen is believed to relieve pain by elevation of the pain threshold and is generally given in amounts ranging from about 600 to 1300 mg per dose in humans.
While acetaminophen is equally effective as aspirin, it is unlikely to produce many of the adverse effects of aspirin and aspirin-containing products. Acetaminophen itself, however, has been associated with a propensity for contributing to liver damage in patients that ingest significant amounts of alcohol. The dose-related toxic effect of acetaminophen on liver is demonstrated by the hepatic toxicity seen with overdosage of acetaminophen. Therefore, it would be desirable to be able to effectively treat pain utilizing lower doses of acetaminophen.
Combinations of various analgesics to provide additive effects in treating pain are known in the literature; e.g., combinations of aspirin with codeine or other narcotic analgesics are known to provide additive analgesic effects in man. See: The Pharmacologic Basis of Therapeutics, 5th edition, Macmillan Publishing Co., 1975, pp. 325-358. More active analgesic combinations are continually sought since they may be able to relieve pain with reduced dosages, thereby diminishing accompanying adverse effects and toxicities resulting from higher dosages. It is particularly desirable to discover an enhancing agent and/or a synergistic combination effect.
Acetaminophen analgesic combinations have been previously disclosed.
Cooper, in U.S. Pat. No. 4,794,112 disclosed combinations of hydroxyzine with acetaminophen as being effective analgesic compositions.
In our earlier disclosure, WO 01/01989, Cloarec, et al. described combinations of buspirone and acetaminophen (paracetamol) as being useful for treating pain. No reports of the use of other azapirones, e.g. gepirone in this regard have been reported.
Two hydroxyazapirones have been disclosed as metabolites of the azapirones buspirone and gepirone.
6-Hydroxybuspirone, chemically: 6-hydroxy-8-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-8-azaspiro(4,5)-decane-7,9-dione is a metabolite of buspirone which was disclosed in U.S. Pat. No. 6,150,365 as being effective for the treatment of anxiety.
3-Hydroxygepirone, chemically: 4,4-dimethyl-3-hydroxy-1-[4-[4-(2-pyrimidinyl)1-piperazinyl]butyl-2,6-piperidinedione is a metabolite of gepirone reported by von Moltke, et al. in Psychopharmacology, 1998,140:293-299.
Neither 6-hydroxybuspirone nor 3-hydroxygepirone have been reported to possess antinociceptive effects. There has been no suggestion in the prior art to combine either of these compounds with acetaminophen to enhance its analgesic effect for the treatment of pain.
The present invention provides a method for treatment of pain comprising the concurrent administration of a hydroxyazapirone consisting of 6-hydroxybuspirone and 3-hydroxygepirone, and acetaminophen in a manner which results in strengthening of the antinociceptive effects of acetaminophen. The analgesia produced by the concurrent administration of acetaminophen and the hydroxyazapirone is more opioid-like, resembling morphine in having a more rapid onset and providing greater pain relief. The concurrent administration of 6-hydroxybuspirone or 3-hydroxygepirone also allows for the use of smaller amounts of acetaminophen, thereby reducing the liver toxicity potential. The present invention also comprises pharmaceutical compositions and pharmaceutical kit/packaging containing acetaminophen and 6-hydroxybuspirone or 3-hydroxygepirone for combination therapy.